Natural history and pathogenesis of Sjogren's syndrome(SS) The primary objective of this study is to enable the collection of longitudinal clinical and laboratory data and biologic specimens to identify pathogenetic mechanisms of SS and other salivary gland dysfunction clinical states by careful clinical phenotyping of SS patients and Sjogrens-like conditions over time and collection of biologic samples for concurrent and future laboratory studies related to the pathogenesis of Sjgrens syndrome. Another objective of the study is to identify biomarker candidates associated with the diagnosis, severity, prognosis, or organ involvement in SS. Associated research projects: 1. Ex-vivo salivary gland functional imaging The molecular mechanisms underlying salivary gland secretory defects in SS is unknown. While the destruction of glandular structure can contribute to the decrease in total salivary fluid secretion, it does not explain the loss of secretion in patients who have low, or negligible, levels of inflammation in the glands (this group constitutes over 80% of the SS patients). By obtaining fresh minor salivary gland biopsies from SS patients and healthy volunteers, we examine single acinar cell function from intact acinar clusters, with confocal microscopy. We are able to measure calcium influx and release in individual cells and also measure individual cell volume changes after agonist stimulation. This has allowed us to focus on specific candidate proteins that might be responsible for the salivary gland dysfunction associated with SS 2.Trancriptome profiling of salivary glands There is an unmet need to characterize the molecular profile of the broad range of phenotypes in SS. With the advent of high throughput sequencing methods, a complete characterization of whole transcriptome of salivary glands and specifically of each of their resident cells types will greatly facilitate the sub-classification and better characterization of the genetic changes in SS patients. In SS the presence of different levels of inflammation in glands of patients present a challenge when whole glands are used as source of material. Under these circumstances, the analysis of genetic material and proteins from heterogeneous tissue sample as a whole, might mask the important changes that occur in the individual types of cells. Laser capture microdissection allows the procurement of specific cell types by dissecting out only cells of interest. We are planning to use parotid and minor salivary glands of SS patients and through laser capture microdissection isolate and characterize the genetic profile of ductal and acinar cells as well as the resident lymphocytes . Through this project proteins will also be isolated from each cell type and stored for future 3. Characterization of Immune Checkpoint Inhibition induced sicca Immunotherapy has provided a needed breakthrough in cancer therapy for a number of malignancies. Immune checkpoint inhibition in some patients leads to durable tumor rejection and increased survival. However, augmenting the immune system can have devastating effects on a number of organ systems. Approximately 25% of patients on drugs targeting the PD-1/PD-L1 co-receptors will experiences severe dry mouth. We are currently investigating the local immune activation in the context of immunotherapy in the salivary gland to gain meaningful mechanistic insight into immune related adverse events duet to immune checkpoint inhibition and rational targets for prevention and treatment.